We previously demonstrated enhanced lymphocyte natural cytotoxicity by interferon (IF) in vitro and after poly I:C treatment in vivo in animal models of carcinogen-induced and transplantable bladder cancer. This was associated with inhibition of tumor growth in both models by poly I:C. Even greater inhibition was seen after treatment with both poly I:C and indomethacin, a prostaglandin synthetase inhibitor. Observations in this instance were correlated with a possible role of macrophages in immune response manipulation and tumor inhibition in these models. The intricacy of these interactions and their effect on tumor development in each model prompted the present proposal to explore the immunologic effects of poly I:C both regionally and in a metastatic model in which immune response manipulation and its effects on tumor at selected sites would be assessed both in intact animals and in animals deficient in selected immune response components. C3H mice naturally deficient in T-cell function (homozygous nudes), macrophage function (HeJ vs HeN), or natural killer cell function (beige), as well as animals treated with silica, carrageenan, cimetidine, and/or specific anti-interferon antisera would be used for study of tumor development in both the carcinogen-induced and metastatic models. Immunologic effects of poly I:C would be assessed by examination of lymphocyte and macrophage cytotoxicity (51Chromium release assay using NK- and T-cell sensitive cell lines), lymphocyte response in mixed lymphocyte- and mixed lymphocyte/tumor cell culture, and changes in lymphocyte subpopulations (immunofluorescent labelling of specific surface markers). Each of these in vitro assessments would be correlated with tumor development and progression in each model. Specific aims of these studies are to characterize further the role of different components of immune response expression on primary regional and systemic tumor development, effects of deficiencies of selected compartments on tumor progression, and effects of poly I:C in the immunologic manipulation of these components on both tumor growth and progression. The relevance of these animal models to both superficially invasive and metastatic disease as seen clinically suggest our long-term objectives which are to determine suitable regimens for adaptation in the treatment of both regional and metastatic bladder cancer in man.